The present invention relates to a method and a system for detecting the onset of atherosclerosis and determining the degree of atherosclerosis in a patient by sensing certain physical parameters of the patient's artery. In one embodiment those parameters are correlated with data obtained from arteries having a measured amount of stenosis or closure of the artery, and further correlating the patient's arterial parameter with certain other physical characteristics such as age, blood pressure and cholesterol levels.
Animal studies have shown significant changes in the mechanical properties of arteries with progression of atherosclerosis, a disease commonly referred to in humans as hardening of the arteries. In an article by J. T. Nichol, "The effect of cholesterol feeding on the distensibility of the isolated thoracic aorta," Can. J. Biochem. Physiol., Vol 33, pp. 507-516, 1955, Nichol determined the effect of cholesterol feeding on the volume-pressure curve of rabbit thoracic aorta. The curves showed a typical characteristic of decreased arterial compliance at higher pressures. He showed that cholesterol feeding of the rabbits decreased peak compliance of vessels during collapse to about 20% of its normal value. An article by T. I. Pynadath and D. P. Mukherjee, "Dynamic mechanical properties of atherosclerotic aorta. A correlation between the cholesterol ester content and the viscoelastic properties of atherosclerotic aorta,"Atherosclerosis, Vol 26, pp. 311-318, 1977 (herein Pynadath and Mukherjee) showed that rabbits on a cholesterol diet had a significantly higher tangential Young's modulus compared to the control group during the early stage of disease. For the aorta, the increase was 33% after a period of 6 weeks on a 1.5% cholesterol diet. An article by D. J. Farrar, H. D. Green, M. G. Bond, W. D. Wagner and R. A. Gobbee, "Aortic Pulse Wave Velocity, Elasticity, and Composition in a Nonhuman Primate Model of Atherosclerosis," Circ. Res., Vol. 43, pp. 52-62, July 1978, (herein Farrar et al.) discloses a study of 13 monkeys (Macaca fascicularis) which were fed either an atherogenic or control diet for 36 months. They found that the aortic pulse wave velocity in the atherosclerotic monkeys was 1.5 to 2 times the values for the control animals. With postmortem studies, they found that the static circumferential distensibility of the excised atherosclerotic aortas was significantly less than the control, but there was no difference in incremental (Young's) modulus of elasticity. They concluded that the significantly increased stiffness of the atherosclerotic arteries appeared to be mainly due to the increased wall thickness caused by the atherosclerotic plaques and perhaps due to extensive medial damage, rather than due to material changes described by Young's modulus. Though Pynadath and Mukherjee and Farrar et al. differed in their conclusion with regard to the changes in the Young's modulus, both results imply stiffer arteries, which were more resistant to collapse and had lower compliance during collapse.
In addition to detection of atherosclerosis, intervention studies of risk factor reduction in humans have been undertaken to determine the extent of regression, if any, with different intervention regimens combining dietary modification, drugs, and exercise programs. A similar conclusion was drawn in an animal study conducted (on abdominal, carotid and coronary arteries) by J. K. Sawyer, as reported in her M. S. thesis (1984) at the Bowman Gray School of Medicine, Winston-Salem, N.C., entitled "A Comparative Quantitative Study of Atherosclerosis in Abdominal Aorta, Coronary and Carotid Arteries of Hypercholestrolemic Macaca Fascicularis." Serial comparison of individual human data is not possible because epidemiologic end points, such as cardiovascular death, significantly affect the data. Serial data for humans is extremely difficult to evaluate when other epidemiological end points are identified, such as myocardial infarction and stroke. The occurrence of myocardial infarction in a human implies that vascular insufficiency has grown worse, and there is no corresponding end point which can be selected to ascertain whether vascular insufficiency has improved. D. H. Blankenhorn, S. Brooks, R. H. Selzer, and R. Barndt, Jr., in an article entitled "The Rate of Atherosclerosis Change during Treatment of Hyperlipoproteinemia," Circulation, Vol. 57, pp. 355-361, February 1978, advocate the use of femoral angiograms (an invasive imaging technique) for serial comparison of lesion size. The relationship of femoral lesion change to long-term cardiovascular mortality rate, however, is not fully known at present. Even though the severity of atherosclerosis in one artery does not predict the severity in another artery for an individual case, on a group basis, the average amount of lesion development in one artery can be correlated with the average amount of lesion involvement in other arteries. See L. A. Solberg and J. P. Strong, "Risk Factors and Atherosclerotic Lesions," Arteriosclerosis, Vol. 3, pp. 187-198, May/June 1983. Researchers have continued to evolve techniques to obtain and decipher electronic images of superficial arteries, such as carotid and femoral arteries, since early detection of atherosclerosis and implementation of an intervention program to reduce atherosclerosis even in one vascular bed may improve the quality of life, reduce economic burdens inherent with atherosclerosis, and prolong the life span of the patient.
Selective angiography, using invasive equipment and electronic imaging techniques, involves significant cost, plus some discomfort and risk to patients. This has led to the development of B-mode ultrasound for noninvasive observation of lesions in the carotid artery and related electronic imaging techniques to evaluate the electronically obtained vascular image. See M. G. Bond, W. A. Riley, R. W. Barnes, J. M. Kaduck, and M. R. Ball, "Validation Studies of a Noninvasive Real Time B-scan Imaging System," in T. F. Budinger, A. S. Berson, I. Ringquist, M. B. Mock, J. T. Watson, and R. S. Powell, eds., Noninvasive Techniques for Assessment of Atherosclerosis in Peripheral, Carotid, and Coronary Arteries, pp. 197-203, New York: Raven Press, 1982. The National Heart, Lung and Blood Institute of the National Institute of Health has initiated a multicenter study which is currently under way to enhance the sensitivity, specificity and signal processing techniques required to perfect B-mode ultrasound detection of the disease. Also, computerized fluoroscopy is an experimental, minimally invasive imaging technique that is being used to characterize arterial lesions. See C. A. Mistretta, R. A. Kruger, D. E. Ergun, C. G. Shaw, M. Van Lysel, C. Strother, A. B. Crummy, J. F. Sackett, W. Zwiebel, D. Myerowitz, W. Turnipseed, and H. Berkoff, Intravenous Angiography Using Fluoroscopy Techniques, in T. F. Budinger, A. S. Berson, Ringquist, II, M. B. Mock, J. T. Watson, and R. S. Powell, eds., Noninvasive Techniques for Assessment of Atherosclerosis in Peripheral, Carotid and Coronary Arteries, p. 71, Raven Press, New York (1984).
Noninvasive techniques for early detection of atherosclerosis are currently being developed with a corresponding ability to follow progression/regression of the disease in humans. These techniques are thus becoming increasingly essential, as new intervention techniques are continually evolving and as the public becomes increasingly aware of the effects of lifestyle on their quality and length of life.
While the electronic imaging techniques have tried to focus on lesions, other techniques have evolved that address the hemodynamic effects and changes in mechanical properties associated with atherosclerosis. Recently an echo-doppler examination coupled with spectral analysis signal processing techniques has been used to study iliac artery stenosis. See P. Rubba, F. Faccenda, B. De Simone, G. Riccardi and M. Mancini, "Validation of echo-Doppler for the Detection of Iliac Artery Stenosis or Occlusion," in R. J. Hegyeli, ed., End Points for Cardiovascular Drug Studies. Vol. 12, Atherosclerosis Reviews, New York: Raven Press, 1984. These authors indicate that the method has many potential sources of errors and much work is needed before the technique is widely accepted and its routine adopted by the medical community. An echo tracking device coupled to B-mode ultrasound equipment has been used to measure the elastic properties of the human abdominal aorta. See T. Imura, K. Yamamoto, K. Kanamori, T. Mikami, and H. Yasuda, "Non-invasive ultrasonic measurement of the elastic properties of the human abdominal aorta," Cardovas. Res., Vol. 20, pp. 208-214, 1986. Imura et al. found that E, the pressure strain elastic modulus, was significantly higher in subjects older than 60 years.
The theory of detecting atherosclerosis based on noninvasive determination of arterial compliance in the leg was studied by T. M. R. Shankar in "The origin of impedance pulse in the limbs and arterial compliance studies using impedance plethysmography," a Ph.D. Dissertation, Department of Electrical and Computer Engineering, University of Wisconsin, Madison, Wis., 1982 (herein the Shankar thesis). The Shankar thesis discloses that the arterial peak compliance in humans decreases with age, hypertension and further decreases with peripheral vascular disease.
In the Shankar thesis, an electrical impedance plethysmography (ZPG) was used to record the impedance pulse .DELTA.Z due to pulsatile blood flow through the artery under study. The impedance pulse was used to calculate the arterial pulse volume .DELTA.V. Further, the compliance value C of the artery under study was computed as the ratio of .DELTA.V to the blood pressure pulse P (obtained using the Korotkoff method: systolic minus phase 5 diastolic pressure). To obtain C at different arterial transmural pressures, a pressure cuff was wrapped around the lower leg of the patient and the cuff pressure was incrementally increased while the impedance pulse was measured. At an external cuff pressure of about 100 mm Hg (slightly higher than the diastolic pressure), the transmural pressure of the artery was near zero and the maximal arterial volume change was recorded. The arterial walls are most flaccid at zero transmural pressure. The maximum ratio of .DELTA.V and .DELTA.P provides the maximal (or peak) compliance C.sub.p. This technique was used to study 118 human subjects. The findings revealed that C.sub.p varied significantly with risk factors for atherosclerotic cardiovascular disease.
In the follow-up pathologic validation study, 20 monkeys were studied. Preliminary results were presented in an article by R. Shankar, M. G. Bond, J. F. Gardin and S. K. Wilmoth, entitled "Noninvasive compliance and morphologic data: An animal study," Proc. Annual Conf. Eng. Biol. Med., Vol. 39, pp. 247, 1986 (herein the Shankar '86 study) and in R. Shankar and M. G. Bond, "Correlation of noninvasive arterial compliance with anatomic pathology of atherosclerotic non-human primates," Poster 852, 8th Int. Symp. Atherosclerosis, Rome, Italy, October, 1988 (herein the '88 Poster). Respective groups of monkeys were fed a cholesterol diet and a control diet for a period of 26 months. The results disclosed in the Shankar '86 study revealed that there was a negative correlation between the peak compliance and the averaged percent of intima in arterial tissue. The results indicate a distinct inverse association for arteries between the absolute amount of atherosclerotic plaque and the peak compliance. However, the Shankar '86 study noted that the correlation was only a rank correlation, that the morphometric measurements were worst case values, and those measurements were not necessarily the values for the arterial section subjected to the non-invasive measurements. The '88 Poster revealed a correlation between the non-invasively measured peak compliance of the monkeys and the actual morphometric data and concluded that (1) peak compliance was significantly lower in atherosclerotic arteries, and (2) peak compliance may be an approximate measure to detect early atherosclerosis.
The method of the present invention is related, in a most general sense, to the invasive procedure adopted by Abboud to determine arterial rigidity. See F. M. Abboud, "The role of vascular stiffness in causing or maintaining elevated blood pressure," Int. Conf. Cardiovascular System Dynamics, edited by J. Baan, A Noordergraaf, J. Raines, Cambridge, Mass.; MIT Press, 1975. Abboud estimated stroke volume using ballistocardiography. He assumed that the arterial volume change was a fixed fraction of the stroke volume. He used an intra-arterial catheter placed in the brachial artery to measure the pressure. He induced vasodilation in huma subjects with amyl nitrite inhalation. This resulted in a slow decrease in the arterial pressure. The pulse pressure also decreased, which indicated a higher compliance. Arteries showed a higher rigidity index (a lower peak compliance) with aging. Subjects with clinical symptoms of atherosclerosis had still higher values of rigidity index
The method of the present invention is also generally related to two other noninvasive techniques: the oscillometric method of blood pressure measurement and pulse volume recording (PVR) In the oscillometric method, a pressure cuff is wrapped around the arm and the cuff pressure oscillations are recorded as the cuff pressure is decreased from suprasystoic or subdiastolic pressure. The oscillations start at systolic pressure, and the amplitude of oscillations increases, reaching maximum near the mean pressure and gradually decreasing below that mean pressure See generally L. A. Geddes, The Direct and Indirect Measurement of Blood Chicago: Year Book Medical Publishers, 1970. The oscillations are proportional to volume changes. If the volume of the air in the cuff is known, one can obtain calibrated volume changes, which should equal values obtained with the impedance plethysmograph. This has been verified for cuff pressures near the mean pressure, where the maximal arterial volume change (and hence C.sub.p) is obtained The difference between outputs from the volume and impedance plethysmographs was typically 3% for leg segments.
Pulse volume recording (PVR) is widely used for the evaluation of subjects with peripheral vascular disease. See R. F. Kempczinski and J. S. T. Yao (eds), Practical Noninvasive Vascular Diagnosis, Chicago: Year Book Medical Publishers, 1987. PVR uses a segmental plethysmograph. In an article by L. H. Griffin, Jr., C. H. Wray and W. H. Moretz, "Immediate assessment of vascular operations using segmental plethysmography," Am. Surgeon. Vol 41, pp. 67-76, 1975), a standardizing device was used. However, this practice does not seem to be common. PVR is mainly used to monitor qualitative changes with progression of peripheral vascular disease. The recording is made at one cuff-pressure, 65 mm Hg, which is typically less than diastolic pressure and where maximal arterial volume change is not recorded.
Mount U.S. Pat. No. 3,835,840 discloses an apparatus and a method for non-invasive measurement of volume rate of flow of blood in an artery. A plethysmograph imparts an excitation to a pair of outer electrodes, bound about a leg or arm, and a pair of inner electrodes are connected to a voltage sensor in the plethysmograph. The plethysmograph outputs a signal which is directly proportional to the impedance of the appendage bound between the electrodes An electrical circuit produces an output value that is essentially proportional to pulsatile arterial flow by taking the time derivative of the plethysmograph output, providing a zero reference value and then integrating the result over a predetermined time. The Mount disclosure states that the accuracy of this system decreases due to hypertension or arterial wall stiffening (arteriosclerosis).
Osanai U.S. Pat. No. 4,432,374 discloses a plethysmograohic acceleration pulse wave meter which measures the increase or decrease in blood volume through a finger apex. The output of a plethysmograph is twice or triply differentiated to produce an acceleration curve.
Wheeler U.S. Pat. No. 4,144,878 discloses an occlusive impedance plethysmograph. The rate at which blood flows out from the venous system immediately following cessation of the forced blockage of the venous return to the heart (venous outflow rate) is correlated with the change in venous volume which accompanies the application of the force blockage (venous capacitance).
Djordjevich U.S. Pat. No. 4,437,469 discloses a system for determining characteristics of blood flow. An impedance plethysmograph is utilized and the signal output therefrom is graphically compared to a signal representing blood pressure changes.
Kuris U.S. Pat. No. 3,577,981 discloses an ultrasonic method for detecting the accumulation of cholesterol.